Dual modulation of cell survival and cell death by β 2 -adrenergic signaling in adult mouse cardiac myocytes

Proceedings of the National Academy of Sciences of the United States of America - Tập 98 Số 4 - Trang 1607-1612 - 2001
Weizhong Zhu1, Minghao Zheng1, Walter J. Koch1, Robert J. Lefkowitz1, Brian K. Kobilka1, Rui‐Ping Xiao1
1Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224; Department of Surgery and Department of Medicine and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710; and Howard Hughes Medical Institute, Stanford University Medical Center, Stanford, CA 94305

Tóm tắt

The goal of this study was to determine whether β 1 -adrenergic receptor (AR) and β 2 -AR differ in regulating cardiomyocyte survival and apoptosis and, if so, to explore underlying mechanisms. One potential mechanism is that cardiac β 2 -AR can activate both G s and G i proteins, whereas cardiac β 1 -AR couples only to G s . To avoid complicated crosstalk between β-AR subtypes, we expressed β 1 -AR or β 2 -AR individually in adult β 1 /β 2 -AR double knockout mouse cardiac myocytes by using adenoviral gene transfer. Stimulation of β 1 -AR, but not β 2 -AR, markedly induced myocyte apoptosis, as indicated by increased terminal deoxynucleotidyltransferase-mediated UTP end labeling or Hoechst staining positive cells and DNA fragmentation. In contrast, β 2 -AR (but not β 1 -AR) stimulation elevated the activity of Akt, a powerful survival signal; this effect was fully abolished by inhibiting G i , G β γ , or phosphoinositide 3 kinase (PI3K) with pertussis toxin, βARK-ct (a peptide inhibitor of G β γ ), or LY294002, respectively. This indicates that β 2 -AR activates Akt via a G i -G β γ -PI3K pathway. More importantly, inhibition of the G i -G β γ -PI3K-Akt pathway converts β 2 -AR signaling from survival to apoptotic. Thus, stimulation of a single class of receptors, β 2 -ARs, elicits concurrent apoptotic and survival signals in cardiac myocytes. The survival effect appears to predominate and is mediated by the G i -G β γ -PI3K-Akt signaling pathway.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 98 Số 4

1607-1612

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